ABSTRACT We propose a study of functional interactions between nuclear receptors in breast cancer cells as a project under this USA-NFSC initiative, with great scientific and intellectual benefit, based on the efforts of two closely- collaborating investigators with shared research interests, but with disparate areas of expertise. Drs. Michael Rosenfeld and Wen Liu have an extensive history of effective collaborations, as evidenced in a number of fundamental discoveries over the past ten years, including nine co-authored papers. This project, involving a sustained, close scientific interaction and collaboration is based on their complementary expertise, focus and resources. We propose to establish an unappreciated, but critical, molecular strategy that serves as the basis for large enhancer-dependent programs of coding target gene transcriptional repression important in breast cancer. This program depends on the fact that ER? is recruited in trans to the basally active enhancers that mediate the repressive transcriptional program, with trans-bound ER? receptor recruiting a demethylase, based on the availability of its DNA binding domain, which in turn recruits machinery leading to dismissal of Pol II from these basally highly active enhancers, causing their repression. This mechanism therefore represents a previously unappreciated type of repressive strategy, and involves a gene set that serves as a powerful prognostic indicator of a ten-year metastasis-free survival. This would uncover a set of largely overlooked prognostic biomarkers for breast cancer patients, perhaps ultimately providing a potential target for treatment or prevention of aggressive breast cancers. A strategy is proposed to underlie the ability of liganded glucocorticoid receptor to inhibit the ER?-activated regulatory enhancers in breast cancer cells, based on competition between different members of the nuclear receptor family.